The candidate is an M.D. who has completed full medical training including clinical hematology/oncology fellowship and is now intensively pursuing basic research with the ultimate goal of a career as an independent investigator. The research will be carried out in the hematology division of a major teaching hospital. The laboratory group focuses on erythroid development, and has expertise in molecular biology and transgenic technology. The research project investigates red cell differentiation and development. Iron deficiency is the leading cause of anemia world wide, with conservative estimates of over 0.5 billion people affected; however, despite this frequency its pathophysiology is incompletely understood. The project outlined focuses on the role of iron in regulating red cell differentiation and development with the goal of increasing understanding of the block to normal erythropoiesis in iron deficiency. The transferrin receptor will be genetically manipulated in murine embryonic stem cells. These cells will be injected into mouse blastocysts and bred to homozygosity to allow in vivo study of the transferrin cycle. If homozygous mice are non-viable chimeric mice will be generated using embryonic stem cells in which both copies of the transferrin receptor have been altered. Experiments are also planned utilizing the technique of in vitro erythroid differentiation of these genetically altered embryonic stem cells. Information learned will lead to increased understanding of the block to red cell production in iron deficiency, and ultimately to the development of new treatment strategies for iron deficiency and iron overload.